The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.
Animal experimentation: All animal procedures met the European Community Directive guidelines (Agreement B33-522-2/ Number DIR 1322) and were approved by the ethical committee from Bordeaux University.
Human subjects: Samples of human lung cancer tissues were obtained from the Haut-Leveque University Hospital (Bordeaux, France) and reviewed by expert pathologist in the field (H. Begueret). These procedures were approved by the Institutional Review Board at Haut-Leveque (NFS96900 Certification).
- Johanna Ivaska, University of Turku, Finland
© 2016, Fessart et al.
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